Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof

ABSTRACT

The present invention relates to novel processes for preparing intermediates of the formula I ##STR1## and to novel intermediates thereof which are useful in the preparation of inhibitors of enkephalinase and angiotensin converting enzyme.

BACKGROUND OF THE INVENTION

This is a continuation-in-part of application Ser. No. 08/360,915, filedDec. 21, 1994, abandoned.

The present invention relates to novel processes for preparing compoundsof the formula I, ##STR2## which are useful intermediates for preparinginhibitors of enkephalinase and angiotensin converting enzyme, including[4S-[4α,7α(R*),12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid and [4S-[4α, 7α(R*),12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid and pharmaceutically acceptable salts thereof (European PatentApplication No. 0 481 522 A1, published 22 Apr. 1992, 209th ACS NationalMeeting, Division of Medicinal Chemistry, Abst. No. 161 (1995), andEuropean Patent Application No. 657 453 A1, published 14 Jun. 1995) andto novel intermediates thereof.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing a compoundof formula I ##STR3## wherein G completes an aromatic ring selected fromthe group consisting of ##STR4## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy;

comprising:

(a) reacting a phthalimido aryl amino acid amide of the formula ##STR5##wherein Ar is a radical selected from the group consisting of ##STR6##wherein X₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl andC₁ -C₄ alkoxy;

with glutaric dialdehyde to give a 1,4-dihydropyridine derivative of theformula ##STR7## wherein Ar is as defined above;

(b) reacting the 1,4-dihydropyridine derivative with an appropriatecyclizing acid to give a 1,2,6,7,8,12bhexahydro-6-oxopyrido[2,1-a][2]azepine of the formula ##STR8## wherein Gis as defined above;

(c) reacting the 1,2,6,7,8,12b hexahydro-6-oxopyrido[2,1-a][2]azepinewith carbon monoxide in the presence of a suitable acid followed byhydration.

In addition, the present invention provides a novel process forpreparing a compound of formula I ##STR9## wherein G completes anaromatic ring selected from the group consisting of ##STR10## wherein X₁is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy;

comprising:

(a) reacting a phthalimido aryl amino acid derivative of the formula##STR11## wherein A is selected from the group consisting of --OH, --Cl,--Br, anhydride, mixed anhydride, and activated ester;

Ar is a radical selected from the group consisting of ##STR12## whereinX₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy phenyl andC₁ -C₄ alkoxy;

with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a2-cyano-1,2,3,4-tetrahydro-pyridine derivative of the formula ##STR13##wherein Ar is as defined above;

(b) reacting the 2-cyano-1,2,3,4-tetrahydro-pyridine derivative with anappropriate cyclizing acid to give a-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine ofthe formula ##STR14## wherein G is as defined above;

(c) hydrolyzing the4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine.

The present invention provides a novel compound of the formula:##STR15## wherein Ar is a radical selected from the group consisting of##STR16## wherein X₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR17## wherein G completes an aromatic ring selected fromthe group consisting of ##STR18## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR19## wherein Ar is a radical selected from the groupconsisting of ##STR20## wherein X₁ is selected from the group consistingof S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR21## wherein G completes an aromatic ring selected fromthe group consisting of ##STR22## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application:

a) the designation ##STR23## refers to a bond that protrudes forward outof the plane of the page; b) the designation ##STR24## refers to a bondthat protrudes backward out of the plane of the page; c) the designation##STR25## refers to a bond for which the stereochemistry is notdesignated; d) the term "C₁ -C₄ alkoxy" refer to a straight or branchedalkoxy group containing from 1 to 4 carbon atoms, such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc;

e) the term "phenyl" refers to a radial of the formula ##STR26## f) thedesignation ##STR27## refers to a thienyl or pyrrolyl and it isunderstood that the radical may be attached at either the 2-position orthe 3-position;

g) the designation ##STR28## refers to an indolyl, benzthienyl, orbenzfuryl and it is understood that the radical may attached at eitherthe 2-position or the 3-position;

h) the designation ##STR29## refers to a naphthyl it is understood thatthe radical can be attached at either the 1-position or the 2-position;

i) it is understood that when G completes an aromatic ring ##STR30##that the compound of formula I is of the formula ##STR31## j) it isunderstood that when G completes an aromatic ring ##STR32## that thecompound of formula I is of the formula ##STR33## k) it is understoodthat when G completes an aromatic ring ##STR34## that the compound offormula I is of the formula ##STR35## l) it is understood that when Gcompletes an aromatic ring ##STR36## that the compound of formula I isof the formula ##STR37## m) it is understood that when G completes anaromatic ring ##STR38## that the compound of formula I is of the formula##STR39## n) it is understood that when G completes an aromatic ring##STR40## that the compound of formula I is of the formula ##STR41## o)it is understood that when G completes an aromatic ring ##STR42## thatthe compound of formula I is of the formula ##STR43## p) the term"pharmaceutically acceptable salts" refers to either acid addition saltsor to base addition salts.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of inhibitors of enkephalinase and angiotensin converting enzyme,including [4S-[4α, 7β(R*),12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid or [4S-[4α, 7β(R*),12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid or any intermediates thereof. Illustrative inorganic acids whichform suitable salts include hydrochloric, hydrobromic, sulphuric, andphosphoric acid and acid metal salts such as sodium monohydrogenorthophosphate, and potassium hydrogen sulfate. Illustrative organicacids which form suitable salts include the mono-, di-, andtricarboxylic acids. Illustrative of such acids are for example, acetic,glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic,and sulfonic acids such as p-toluenesulfonic acid, methane sulfonic acidand 2-hydroxyethane sulfonic acid. Such salts can exist in either ahydrated or substantially anhydrous form.

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of inhibitors of enkephalinase and angiotensin converting enzyme,including [4S-[4α, 7β(R*),12bβ]]-7-[(1-oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid or [4S-[4α, 7β(R*),12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid or any intermediates thereof. Illustrative bases which formsuitable salts include alkali metal or alkaline-earth metal hydroxidessuch as sodium, potassium, calcium, magnesium, or barium hydroxides;ammonia, and aliphatic, cyclic, or aromatic organic amines such asmethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,isopropyldiethylamine, pyridine and picoline.

As is appreciated by one of ordinary skill in the art, the methodologydisclosed herein can be used to prepare all isomers at the 4-positionand 7-postition of instant intermediates, including7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid and thereby the isomers of the inhibitors of enkephalinase andangiotensin converting enzyme produced therefrom. The stereochemistry atthe 7-position of the intermediates is determined by the stereochemistryof the phthalimido aryl amino acid amide or the activated phthalimidoaryl amino acid derivative selected. The specific 4-positionstereoisomers can be resolved and recovered by techniques known in theart, such as chromatography on silica gel or on a chiral stationaryphase, or fractional recrystallization of the 4-position carboxylicacids or derivatives thereof as described herein; in European PatentApplication No. 0 481 522 A1, published 22 April 1992; Stereochemistryof Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994); and inEnantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S.H. Wilen, Wiley (1981).

A general synthetic procedure is set forth in Scheme A. In Scheme A, allsubstituents unless otherwise indicated, are as previously defined.Starting materials, reagents, techniques and procedures used in Scheme Aare well known and appreciated by one of ordinary skill in the art.##STR44##

In Scheme A, step 1, an appropriate phthalimido aryl amino acidderivative of structure (1) is contacted with ammonia to give aphthalimido aryl amino acid amide of structure (2) as is well known inthe art.

In Scheme A, step a, an appropriate phthalimido aryl amino acid amide ofstructure (2) is contacted with glutaric dialdehyde to give a1,4-dihydro-pyridine derivative of structure (3).

An appropriate phthalimido aryl amino acid amide derivative of structure(2) are readily available or are readily derived from aromatic aminoacids which are well known in the art. Examples of aromatic amino acidswhich are useful in this instant process include: phenylalanine,tryptophan, tyrosine and its ether derivatives, thien-2-ylalanine,3-thienylalanine, fur-2-ylalanine, fur-3-ylalanine,benzthien-2-ylalanine, indol-2-ylalanine, etc. The Peptides, vol. 5, E.Gross and J. Meienhoffer ed. (Academic Press, 1983). In addition,aromatic amino acids can be obtained by methods known in the art oranalogously known in the art, such as D. A. Evans, et al. J. Am. Chem.Soc., 112, 4011-4030 (1990); S. Ikegami et al. Tetrahedron 44, 5333-5342(1988); W. Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis ofOptically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposiain print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schollkopf, PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44,3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978);M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnellet al. J. Am. Chem. Soc. 110, 8520-8525 (1988).

An appropriate phthalimido aryl amino acid amide of structure (2) is onein which the stereochemistry is as desired in the final product and Aris as required to give G as desired in the final product. It isunderstood that glutaric dialdehyde can be generated in the reactionmixture from a suitable glutaric dialdehyde equivalent. Suitableglutaric dialdehyde equivalents include acetals of glutaric dialdehyde,hydrated forms of glutaric dialdehyde, and the like.

For example, an appropriate phthalimido aryl amino acid amide ofstructure (2) is contacted with from about 0.9 to 1.2 molar equivalentsof glutaric dialdehyde. The reaction is carried out in a suitablesolvent, such as dichloromethane. The reaction is carried out underacidic catalysis. Suitable catalysts are well known in the art andinclude p-toluenesulfonic acid. The reaction is carried out at fromambient temperature to the refluxing temperature of the solvent. Thereaction is carried out with the removal of water by methods well knownin the art, such as by azeotrope, by passing the refluxate over orthrough a drying agent, such as phosphorous pentoxide or by carrying outthe reaction in the presence of a suitable non-reactive drying agent,such as 3Å molecular sieves, 4Å molecular sieves, MgSO₄, and the like.Generally, the reaction requires from 2 hours to 4 days. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, chromatography, and recrystallization.

In Scheme A, step b, an appropriate 1,4-dihydro-pyridine derivative ofstructure (3) is contacted with an appropriate cyclizing acid to give a1,2,6,7,8,12b hexahydro-6-oxopyrido[2,1-a][2]azepine of structure (4).

For example, an appropriate 1,4-dihydro-pyridine derivative of structure(3) is contacted with an appropriate cyclizing acid. An appropriatecyclizing acid is one which allows for the formation of product withoutleading to significant degradation of either the starting material orthe product. Examples appropriate cyclizing acids include, sulfuricacid, trifluoromethanesulfonic acid, sulfuric acid/trifluoroaceticanhydride mixtures, and trifluoromethanesulfonic acid/trifluoroaceticanhydride mixtures. The reaction is carried out neat in the appropriatecyclizing acid selected or in a suitable aprotic solvent, such asdichloromethane. The reaction is carried out at temperatures of from 10°C.-40° C. Generally the reaction requires from 1 to 8 hours. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography, and recrystallization.

In Scheme A, step c, an appropriate 1,2,6,7,8,12bhexahydro-6-oxopyrido[2,1-a][2]azepine of structure (4) is contactedwith carbon monoxide in the presence of a suitable acid followed byhydration to give a compound of the formula I.

For example, an appropriate 1,2,6,7,8,12bhexahydro-6-oxopyrido[2,1-a][2]azepine of structure (4) is contactedwith an excess of carbon monoxide in the presence of a suitable acid,such as sulfuric acid, followed by hydration. The reaction is carriedout using the suitable acid selected as solvent. The reaction may becarried out in a suitable pressure vessel to prevent the escape ofcarbon monoxide. Carbon monoxide may be introduced as a gas or may begenerated in the reaction vessel by methods well known in the art, suchas the decomposition of formic acid. The reaction is carried out attemperatures of from 0° to 100° C. The reaction may be carried out atpressures of from atmospheric pressure to 900 psi. When the reaction iscarried out at a pressure which is greater than atmospheric the use of asuitable pressure vessel, such as sealed or sealable tubes, a pressurereactor or an autoclave, is required. Generally the reaction requiresfrom 1 to 48 hours. The addition of carbon monoxide is followed byhydration which is accomplished by the addition of water. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography, and recrystallization.

A general synthetic procedure is set forth in Scheme B. In Scheme B, allsubstituents unless otherwise indicated, are as previously defined.Starting materials, reagents, techniques, and procedures used in SchemeB are well known and appreciated by one of ordinary skill in the art.##STR45##

In Scheme B, step a, an appropriate phthalimido aryl amino acidderivative of structure (1) is contacted with2-cyano-1,2,3,4-tetrahydro-pyridine to give a2-cyano-1,2,3,4-tetrahydro-pyridine derivative of structure (6).

An appropriate phthalimido aryl amino acid derivative are readilyavailable or are readily derived from aromatic amino acids which arewell known in the art as described in Scheme A, step a.

An appropriate phthalimido aryl amino acid derivative is one in whichthe stereochemistry is as desired in the final product, Ar is asrequired to give G as desired in the final product, and the group A isan activating group which can be displaced by2-cyano-1,2,3,4-tetrahydro-pyridine in an amidation reaction. Anamidation reaction may proceed through an acid, A is --OH; or an acidhalide, such as an acid chloride, A is --Cl; or acid bromide, A is --Br;or an activated intermediate; such as an anhydride; or a mixed anhydrideof substituted phosphoric acid, such as dialkylphosphoric acid,diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylicacid, such as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroaceticacid, trifluoroacetic acid, and the like; of aromatic carboxylic acids,such as benzoic acid and the like; of an activated ester, such as phenolester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenolester, pentachlorophenol ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester, and thelike; activated amide, such as imidazole, dimethylpyrazole, triazole, ortetrazole; or an intermediate formed in the presence of coupling agents,such as dicyclohexylcarbodiimide or1-(3-dimethyaminopropyl)-3-ethylcarbodiimide. Acid halides and activatedintermediates may be prepared and used without isolation. Alternately,acid halides and activated intermediates may be prepared and isolatedbut not purified before use. The use and formation of acid halides andactivated intermediates is well known and appreciated in the art.

For example, an appropriate phthalimido aryl amino acid derivative ofstructure (1) in which A is --Cl is contacted with a molar excess of2-cyano-1,2,3,4-tetrahydro-pyridine which can be generated in situ byreacting 2,6-dicyano-piperidine with a suitable base such as potassiumt-butoxide. The reaction is carried out in a suitable solvent, such as,tetrahydrofuran. The amide formation reaction is carried out using asuitable base, such as N-methylmorpholine. The reaction is carried outat temperatures of from -50° C. to 40° C. and generally requires from 1hour to 5 hours. The product can be isolated and purified by techniqueswell known in the art, such as filtration, evaporation, extraction,chromatography, and recrystallization.

In Scheme B, step b, an appropriate 2-cyano-1,2,3,4-tetrahydro-pyridinederivative of structure (6) is contacted with an appropriate cyclizingacid to give a4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine ofstructure (7).

An appropriate cyclizing acid is one which allows for the formation ofproduct without leading to significant degradation of either thestarting material or the product. Examples of appropriate cyclizingacids include, sulfuric acid, trifluoromethanesulfonic acid, sulfuricacid/trifluoroacetic anhydride mixtures, and trifluoromethanesulfonicacid/trifluoroacetic anhydride mixtures.

For example, an appropriate 2-cyano-1,2,3,4-tetrahydro-pyridinederivative of structure (6) is contacted with an appropriate cyclizingacid. The reaction is carried out neat in the appropriate cyclizing acidselected or in a suitable aprotic solvent, such as dichloromethane. Thereaction is carried out at temperatures of from 10° C.-40° C. andgenerally requires from 1 to 18 hours. It is preferred that the productof this step, obtained in solution, be used without isolation, however,the product can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

In Scheme B, step c, an appropriate4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine ofstructure (7) is hydrolyzed to give a compound of the formula I.

For example, an appropriate4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine ofstructure (7) is contacted with water. The reaction is carried out inthe presence of a suitable acid catalyst. A suitable acid catalyst isone which allows for the hydrolysis of a cyano group, under the reactionconditions, to a carboxylic acid without removing the phthalimide groupor hydrolyzing the cyclic amide bond. Suitable acid catalysts are wellknown in the art and include, sulfuric acid, trifluoromethanesulfonicacid, trifluoromethanesulfonic acid/trifluoroacetic acid mixtures andsulfuric acid/trifluoroacetic anhydride mixtures. When the product ofthe previous step is used without isolation the appropriate cyclizingacid selected may be used as the suitable acid catalyst for thehydrolysis. The reaction is carried out at temperatures of from about10° C. to about 40° C. Generally the reaction requires from 10 minutesto 2 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

The following examples present typical syntheses as described in SchemesA and B. These examples and preparations are understood to beillustrative only and are not intended to limit the scope of theinvention in any way. As used in the following examples andpreparations, the following terms have the meanings indicated: "mg"refers to milligrams, "g" refers to grams, "kg" refers to kilograms,"mmol" refers to millimoles, "mol" refers to moles, "μL" refers tomicroliters, "mL" refers to milliliters, "L" refers to liters, "°C."refers to degrees Celsius, "mp" refers to melting point, "dec" refers todecomposition, "[α]² _(D) ⁰ " refer to specific rotation of the D lineof sodium at 20° C. obtained in a 1 decimeter cell, "c" refers toconcentration in g/100 mL, "M" refers to molar, "L" refers to liter,"2-PrOH" refers to isopropanol, "MeOH" refers to methanol, "R_(f) "refers to retention factor, "TLC" refers to thin layer chromatography,"psi" refers to pounds per square inch.

PREPARATION 1 Synthesis of N-Phthaloyl-(S)-phenylalanine, acid chloride

Combine phthalic anhydride (1.82 kg, 12.3 mole), (S)-phenylalanine (1.84kg, 11.1 moles) and anhydrous dimethylformamide (2.26 L). Stir at115°-120° C. for 2 hours under a nitrogen atmosphere. Pour into rapidlystirred water (32.6 L) and cool overnight at 0° C. Filter, wash withcold water (2×2 L), and air dry. Dissolve in a mixture of 9A ethanol(8.05 L) and water (8.05 L) and heat at reflux temperature. Gravityfilter, cool to ambient temperature and refrigerate overnight at about0° C. Filter the crystallized product, wash with cold 50:50 9Aethanol/water (2×2 L) and air dry to yield 2.96 kg (90.3%) ofN-phthaloyl-(S)-phenylalanine; mp 177°-179° C.

Combine N-phthaloyl-(S)-phenylalanine (50.2 g, 0.17 mol), methylenechloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogenatmosphere. Add oxalyl chloride (17.7 mL, 0.2 mol) over about 5 minutes.Stir at ambient temperature for 3 hours and evaporate the solvent invacuo to give the title compound.

PREPARATION 2 Synthesis of Phthalimido-(S)-phenyalanine amide ##STR46##

Combine N-phthaloyl-(S)-phenylalanine, acid chloride (100 mmol) andhexane (100 mL). Add a concentrated aqueous ammonia solution (30 mL) andstir rapidly. After 10 minutes, filter, rinse with diethyl ether andwater, and dry in vacuo to give the title compound as a solid.

PREPARATION 3 Synthesis of 2,6-Dicyano-piperidine

Combine sodium cyanide (12.25 g, 250 mmol) and water (40 mL). Addammonium chloride (20 g, 374 mmol) and 30% aqueous ammonia solution (35mL, 620 mmol). Cool in an ice-bath. Add glutaric dialdehyde (25 mL, 50%in water, mmol). After 7 hours in an ice bath, cool in a bath using aice/methanol mixture to form a solid. Collect the solid by filtration,rinse with water, and dry to give the title compound.

EXAMPLE 1(S)-N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine##STR47##

Combine phthalimido-(S)-phenyalanine amide (3.0 g, 10 mmol) and asolution of glutaric dialdehyde (2.0 g, 50% by weight in water) indichloromethane (200 mL). Heat to reflux with azeotropic removal ofwater from the refluxate. Add p-toluenesulfonic acid (60 mg). Continueheating at reflux. Pass the refluxate through oven dried 4Å molecularsieves. After 4 days, cool the reaction mixture to ambient temperature.Extract with 5% sodium bicarbonate solution. Extract the 5% sodiumbicarbonate solution with dichloromethane. Combine the organic layersand dry over Na₂ SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 5%tetrahydrofuran/dichloromethane to give the title compound.

EXAMPLE 1.1(S)-N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine

Combine phthalimido-(S)-phenylalanine amide (6.0 g, 20 mmol) and asolution of glutaric dialdehyde (4.0 mL, 50% by weight in water) indichloromethane (300 mL). Heat to reflux with azeotropic removal ofwater from the refluxate using a Dean-Stark trap. Add p-toluenesulfonicacid (600 mg). Continue heating at reflux with azeotropic removal ofwater. Replace the Dean-Stark trap with a Soxhlet extractor charged withphosphorous pentoxide and continue heating at reflux. After 24 hours,cool the reaction mixture to ambient temperature. Add basic alumina toform a slurry. Filter the slurry through a plug of silica gel and elutewith dichloromethane. Evaporate the filtrate in vacuo to give the titlecompound.

EXAMPLE 2(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-V1)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine##STR48##

Add a solution of(S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine(1.1 g, 3.1 mmol) in dichloromethane (2 mL) to trifluoromethanesulfonicacid (1.2 mL). After 2.5 hours, add trifluoromethanesulfonic acid (1.2mL). After 4 hours, partition the reaction mixture between ethyl acetateand 5% sodium bicarbonate solution. Dry the organic layer over Na₂ SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with 10% ethyl acetate/hexaneand then 25% ethyl acetate/hexane to give the title compound.

EXAMPLE 2.1(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine

Combine sulfuric acid (3.0 mL, 96%) and trifluoroacetic anhydride (300mL). Add(S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine(1.0 mmol). After 30 minutes, pour the reaction mixture into a mixtureof saturated aqueous sodium bicarbonate and ice. Extract with ethylacetate and then with methylene chloride. Combine the organic layers andfilter through a plug of silica gel. Rinse the silica gel withdichloromethane. Evaporate the filtrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 10%ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the titlecompound.

EXAMPLE 3(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8f12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid ##STR49##

Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (32 mg, 0.09mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressure vessel. Add 96%formic acid (200 μL) and quickly seal the vessel. After 18 hours, addwater (10 mL). Extract the reaction mixture with ethyl acetate. Extractthe organic layer with saturated aqueous potassium carbonate solution(5×10 mL). Combine the aqueous layers and carefully acidify with aqueous12M hydrochloric acid solution. Extract with chloroform (5×15 mL).Combine the organic layers, dry over MgSO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 2/1 ethyl acetate/hexane containing 0.5% acetic acid to give thetitle compound. R_(f) =0.14 (silica gel, 2/1 ethyl acetate/hexanecontaining 0.5% acetic acid).

EXAMPLE 3.1(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid

Combine(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine(67 mg, 0.19 mmol) and sulfuric acid (2.0 mL, 95-98%) in a pressurevessel. Add 96% formic acid (400 μL) and quickly seal the vessel. After18 hours, open the vessel cautiously and add ice-cold water (5 mL).Extract the reaction mixture repeatedly with chloroform. Combine theorganic layers, dry over MgSO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 2/1/0.01ethyl acetate/hexane/acetic acid to give the title compound.

EXAMPLE 3.2(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid

Combine(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine(32 mg, 0.09 mmol) and sulfuric acid (1.0 mL, 95-98%) in a pressurevessel. Add carbon monoxide (gas) by sparge to a pressure of 45 psi.After 18 hours, add water (10 mL). Extract the reaction mixture withethyl acetate. Extract the organic layer with saturated aqueouspotassium carbonate solution (5×10 mL). Combine the aqueous layers andcarefully acidify with aqueous 12M hydrochloric acid solution. Extractwith chloroform (5×15 mL). Combine the organic layers, dry over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel to give the title compound.

EXAMPLE 3.3(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid

Combine(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine(800 mg, 2.2 mmol) and sulfuric acid (24 mL) in a pressure vessel.Carefully, add formic acid (4.0 mL, 87 mmol) to minimize mixing andthereby the formation of carbon monoxide. Seal the pressure vessel andadd carbon monoxide to 300 psi before stirring. (Caution, upon mixing asharp rise in pressure will occur.) After 16 hours, vent the vessel andadd the reaction mixture to an ice/water mixture (160 mL). Extractrepeatedly with ethyl acetate. Combine the organic layers and extractrepeatedly with aqueous 10% potassium bicarbonate solution. Combine thepotassium bicarbonate solution layers and cool in an ice-bath. Acidifyto pH 1 using aqueous 6M hydrochloric acid solution. Extract theacidified aqueous layer repeatedly with ethyl acetate. Combine theorganic layers and extract with saturated aqueous sodium chloridesolution, dry over MgSO₄, filter, and evaporate in vacuo to give thetitle compound.

EXAMPLE 4 Synthesis ofN-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydro-pyridine##STR50##

Generate 2-cyano-1,2,3,4-tetrahydro-pyridine in situ, combine2,6-dicyano-piperidine (1.0 g, 7.4 mmol) tetrahydrofuran (20 mL). Coolto about -23° C. using a dry ice/carbon tetrachloride bath. Slowly, addpotassium t-butoxide (0.913 g, 95%, 8.14 mmol). Slow addition of thepotassium t-butoxide is required to minimize the formation ofby-products. After the addition of potassium t-butoxide is complete, thereaction mixture is stirred for 20-30 minutes to give a solution of2-cyano-1,2,3,4-tetrahydro-pyridine. Warm the solution to ambienttemperature. Add N-phthaloyl-(S)-phenylalanine, acid chloride (2.55 g,8.14 mmol) and N-methylmorpholine (0.8 mL, 7.4 mmol). After 2 hours,partition the reaction mixture between chloroform and and aqueous 1Msodium bicarbonate solution. Separate the organic layer, dry over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 25% ethyl acetate/hexane to give thetitle compound.

EXAMPLE 5 Synthesis of4-cyano-(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine##STR51##

CombineN-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-2-cyano-1,2,3,4-tetrahydro-pyridine(100 mg, 0.26 mmol), sulfuric acid (3 mL, 99.999%), and trifluoroaceticanhydride (0.03 mL). After 24 hours, the title compound is obtained as asolution.

EXAMPLE 6(S)-7-[(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-(S)-4-carboxylicacid

Combine a solution of4-cyano-(S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepineas obtained in Example 5 and water (30 mL). After 3 hours, extract thereaction mixture with chloroform. Separate the organic layer, dry overNa₂ SO₄, filter, and evaporate in vacuo to give a residue (10:1 mixtureof S:R isomers at the 4-position carboxylic acid as determined by NMRanalysis). Chromatograph the residue on silica gel eluting sequentiallywith ethyl acetate and then ethyl acetate/acetic acid 99/1 to give thetitle compound. [α]² _(D) ⁰ =-60.74° (c=0.915, MeOH)

PREPARATION 4 Preparation of [4S-[4α, 7α(R*),12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid Synthesis of [4S-[4α, 7α(R*),12bβ]]-7-(Amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid

Combine [4S-[4α,7α(R*),12bβ]]-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a][2]benzazepine-4-carboxylicacid (1.63 kg, 4.03 mol), triethylamine (429 g, 4.24 mol), and methanol(5.59 kg). Add hydrazine monohydrate (241 g, 4.82 mol). Heat at reflux.After 3 hours, cool to 60° C. and pour the reaction mixture into amixture of water (7.326 kg) and aqueous 37% hydrochloric acid solution(821 g). Evaporate in vacuo at 50° C. until the reaction mixture isreduced about 7.8 kg. Dilute the reaction mixture with water (8.078 kg)and adjust the pH to about 2.82 using aqueous 37% hydrochloric acidsolution. Heat to 50° C. After 1 hour, filter to remove the solids andrinse with water (pH adjusted to 2.5 with hydrochloric acid, 1.502 kg).Combine the filtrate and the rinse. Adjust the pH to 7.22 usingtriethylamine. Evaporate in vacuo at 60° C. until the reaction mixtureis reduced to about 4.65 kg to obtain a slurry. Dilute the slurry withisopropanol (3.53 kg) and stir for 30 minutes. Cool to 5° C. to obtain asolid. Collect the solid by filtration, rinse with isopropanol, and dryto give the title compound (933 g, 84.4%).

Synthesis of [4S-[4α, 7'(R*),12bβ]]-7-[(1-Oxo-2(R)-bromo-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid

Mix 3-phenyl-2(R)-bromopropionic acid (967 g, 4.22 mol), tetrahydrofuran(7.74 kg) and N-hydroxysuccinimide (607 g, 5.27 mol) and cool to 5° C.Add, by slow addition over 2.5 hours, a solution of1,3-dicyclohexylcarbodiimide (828 g, 4.01 mol) in tetrahydrofuran (1.936kg), maintaining the temperature between -3° and 3° C. Stir for 19hours, remove 2,3-dicyclohexylurea by vacuum filtration and wash thefilter cake with tetrahydrofuran (1.927 kg). Place the filtrate and washin a 50 L bottom-drain round-bottom flask, add [4S-[4', 7'(R*),12bβ]]-7-(amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid (869 g, 3.17 mol) and stir at 22° C. for 5.5 hours. Addtriethylamine (77 g, 0.76 mol) and stir for an additional 17 hours at22° C. Dilute with ethyl acetate (10.427 kg), wash with water (9.94 kg)with 37% hydrochloric acid (214.2 g) and sodium chloride (418 g), thenwith 12.328 kg water with sodium chloride (418 g). Dry (MgSO₄), filterand wash the filter cake with ethyl acetate (2.193 kg). Evaporate thesolvent in vacuo, add isopropanol (4.210 kg), stir at 12°-16° C. for 17hour, chill and isolate the product by vacuum filtration. Wash withisopropanol (621 g) and dry to give the title compound (940 g, 61%).

Synthesis of [4S-[4α, 7β(R*),12bβ]]-7-[(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid

Mix [4S-[4β, 7α(R*),12bβ]]-7-[(1-oxo-2(R)-bromo-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid (1.052 kg, 2.17 mol), acetone (13.256 kg) and thiolacetic acid(207.1 g, 2.72 mol). Cool to -2° C. and add, over approximately 10minutes, a solution of potassium hydroxide (279.5 g) in water (270 g).Stir at -4° C. for 23 hours, add 1.054 kg water containing 37%hydrochloric acid (210 g) and evaporate the solvent in vacuo. Dissolvethe solid residue in toluene (11.517 kg) at 43° C., transfer to a 22 Lbottom-drain round bottom flask and wash with water (4.067 kg). Wash at41° C. with 4.099 kg water containing sodium chloride (213 g). Evaporatethe solvent in vacuo, dissolve the solid residue in toluene (10.239 kg),filter and cool. After cooling to -2° C., collect the solid by vacuumfiltration, wash with toluene (1.103 kg) and dry under vacuum at up to80° C. to give the title compound (859 g, 82.5%).

Preparation of [4S-[4α, 7α(R*),12bβ]]-7-[(1-Oxo-2(S)-thio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid

Dissolve [4S-[4α, 7'(R*),12bβ]]-7-[(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido[2,1-a][2]benzazepine-4-carboxylicacid (57 mg, 0.12 mmol) in deoxygenated methanol (3 mL) containinglithium hydroxide (0.25 mL, 1M in water, 0.25 mmol). Stir for 30 minutesunder argon atmosphere at ambient temperature. Reduce in volume to 1.5mL in vacuo, then add, by dropwise addition, to a rapidly stirringsolution of 2M hydrochloric acid (2 mL). Collect the resultingprecipitate, wash with water and dry in a vacuum dessicator for 1 hour.Dry at 35° C. overnight to give the title compound as a whiteelectrostatic powder.

What is claimed is:
 1. A process for preparing a compound of the formula##STR52## wherein G completes an aromatic ring selected from the groupconsisting of ##STR53## wherein X₁ is selected from the group consistingof S and NH;X₂ is selected from the group consisting of S, O, and NH;and R is selected from the group consisting of hydrogen, hydroxy,phenyl, and C₁ -C₄ alkoxy; comprising: (a) reacting a phthalimido arylamino acid amide of the formula ##STR54## wherein Ar is a radicalselected from the group consisting of ##STR55## wherein X₁ is selectedfrom the group consisting of S and NH; X₂ is selected from the groupconsisting of S, O, and NH; and R is selected from the group consistingof hydrogen, hydroxy, phenyl and C₁ -C₄ alkoxy;with glutaric dialdehydeto give a 1,4-dihydropyridine derivative of the formula ##STR56##wherein Ar is as defined above; (b) reacting the 1,4-dihydropyridinederivative with an appropriate cyclizing acid to give a 1,2,6,7,8,12bhexahydro-6-oxopyrido[2,1-a][2]azepine of the formula ##STR57## whereinG is as defined above; (c) reacting the 1,2,6,7,8,12bhexahydro-6-oxopyrido[2,1-a][2]azepine with carbon monoxide in thepresence of a suitable acid followed by hydration.
 2. A processaccording to claim 1 wherein the appropriate cyclizing acid is atrifluoromethanesulfonic acid/trifluoroacetic anhydride mixture.
 3. Aprocess according to claim 1 wherein the appropriate cyclizing acid issulfuric acid/trifluoroacetic anhydride mixture.